We propose to conduct a large, cost-effective, randomized, double-blind, placebo-controlled, 2x2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol]) and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements in the primary prevention of cancer and cardiovascular disease (CVD). Data from laboratory studies, epidemiologic research, small primary prevention trials, and/or large secondary prevention trials strongly suggest that these nutritional agents reduce cancer or CVD risk, but large primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. Growing enthusiasm for supplemental vitamin D and fish oil underscores the urgent need for a timely initiation of such a trial, before their use becomes so prevalent (through supplements and fortification of the food supply) as to render participant recruitment and hypothesis testing impossible. The proposed trial will be conducted among 20,000 men aged e60 and women aged e65, to be recruited from a mailing to 1.2 million persons, including health and other professionals, members of AARP (formerly known as the American Association of Retired Persons), and others. The mailing will contain a letter describing the trial, an informed consent form, and a questionnaire soliciting information on past medical history, cancer and vascular risk factors, diet, and medication and nutritional supplement use. Willing and eligible respondents will be enrolled in a 3-month run-in, during which they will receive placebos. At the end of the run-in, those who remain willing and eligible, and who report having taken at least two-thirds of the pills, will be randomly assigned to one of four treatment groups for 5 years: vitamin D3 (1600 IU/d) and fish oil (EPA+DHA, 1 g/d); vitamin D3 and fish oil placebo; placebo vitamin D3 and fish oil; and placebo vitamin D3 and placebo fish oil. Blood samples will be collected and stored to allow assessment of effect modification by baseline 25-hydroxyvitamin D and omega-3 fatty acid levels, as well as future ancillary studies of genetic/biochemical hypotheses. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects, and incidence of endpoints. Endpoints will be confirmed by medical record review. Given our success with prior mail-based large simple trials and cohort studies, as well as results of a pilot study in the intended source population, we believe the trial will be able to provide either definitive positive or informative null results regarding the study hypotheses. PUBLIC HEALTH RELEVANCE: The purported health benefits of vitamin D and marine omega-3 fatty acids are receiving increasing attention in the medical literature and the popular press. However, definitive data on health benefits and risks of these agents are lacking. Findings from this large clinical trial will clarify the role of vitamin D and marine omega-3 fatty acid supplements in the primary prevention of cancer and cardiovascular disease in men and women.